GPR35 explained

G protein-coupled receptor 35 also known as GPR35 is a G protein-coupled receptor which in humans is encoded by the GPR35 gene.[1] Heightened expression of GPR35 is found in immune and gastrointestinal tissues, including the crypts of Lieberkühn.

Ligands

Endogenous ligands

Although GPR35 is still considered an orphan receptor, there have been attempts to deorphanize it by identifying endogenous molecules that can activate the receptor. All of the currently proposed ligands are either unselective towards GPR35, or they lack high potency, a characteristic feature of natural ligands.[2] The following list includes the most prominent examples:

Synthetic agonists

Other synthetic agonists of GPR35 include:

Zaprinast is currently the gold standard in the biochemical evaluation of novel synthetic GPR35 agonists, because it remains potent in an animal model. Most other known agonists display high selectivity towards the human GPR35 orthologue. This phenomenon is well established for other GPCRs and complicates the development of pharmaceutical drugs.[10] [11]

Antagonists

Antagonists of GPR35 include:

Both ML145 and ML144 unfurl their antagonistic activity through inverse agonism. They are, however, highly species-selective, and practically inactive at the rodent receptor orthologues.[13]

Clinical significance

Deletion of GPR35 gene may be responsible for brachydactyly mental retardation syndrome and is mutated in 2q37 monosomy and 2q37 deletion syndrome.[14] In one study GPR35 has been recognised as a potential oncogene in stomach cancer.[15]

Notes and References

  1. O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF, George SR . Discovery of three novel G-protein-coupled receptor genes . Genomics . 47 . 2 . 310–313 . January 1998 . 9479505 . 10.1006/geno.1998.5095 .
  2. Divorty N, Mackenzie AE, Nicklin SA, Milligan G . G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease . Frontiers in Pharmacology . 6 . 41 . 2015-03-10 . 25805994 . 4354270 . 10.3389/fphar.2015.00041 . Frontiers Media SA . free .
  3. Zhao P, Sharir H, Kapur A, Cowan A, Geller EB, Adler MW, Seltzman HH, Reggio PH, Heynen-Genel S, Sauer M, Chung TD, Bai Y, Chen W, Caron MG, Barak LS, Abood ME . Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity . Molecular Pharmacology . 78 . 4 . 560–568 . October 2010 . 20826425 . 2981393 . 10.1124/mol.110.066746 . American Society for Pharmacology & Experimental Therapeutics (ASPET) .
  4. Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L . Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35 . The Journal of Biological Chemistry . 281 . 31 . 22021–22028 . August 2006 . 16754668 . 10.1074/jbc.M603503200 . free . free fulltext
  5. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS, Davenport AP, Brown AJ, Green A, Wigglesworth MJ, Rees S . Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors . Journal of Biomolecular Screening . 18 . 5 . 599–609 . June 2013 . 23396314 . 10.1177/1087057113475480 . SAGE Publications . free .
  6. Deng H, Hu H, Fang Y . Multiple tyrosine metabolites are GPR35 agonists . Scientific Reports . 2 . 1 . 373 . 2012-04-20 . 22523636 . 3330681 . 10.1038/srep00373 . Springer Nature . 2012NatSR...2E.373D .
  7. Yang Y, Lu JY, Wu X, Summer S, Whoriskey J, Saris C, Reagan JD . G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium . Pharmacology . 86 . 1 . 1–5 . 2010 . 20559017 . 10.1159/000314164 . S. Karger AG . 9421354 .
  8. Taniguchi Y, Tonai-Kachi H, Shinjo K . Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35 . FEBS Letters . 580 . 21 . 5003–5008 . September 2006 . 16934253 . 10.1016/j.febslet.2006.08.015 . 43142927 .
  9. MacKenzie AE, Caltabiano G, Kent TC, Jenkins L, McCallum JE, Hudson BD, Nicklin SA, Fawcett L, Markwick R, Charlton SJ, Milligan G . The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35 . Molecular Pharmacology . 85 . 1 . 91–104 . January 2014 . 24113750 . 3868900 . 10.1124/mol.113.089482 .
  10. Thimm D, Knospe M, Abdelrahman A, Moutinho M, Alsdorf BB, von Kügelgen I, Schiedel AC, Müller CE . Characterization of new G protein-coupled adenine receptors in mouse and hamster . Purinergic Signalling . 9 . 3 . 415–426 . September 2013 . 23608776 . 3757137 . 10.1007/s11302-013-9360-9 . Springer Nature .
  11. Gütschow M, Schlenk M, Gäb J, Paskaleva M, Alnouri MW, Scolari S, Iqbal J, Müller CE . Benzothiazinones: a novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives . Journal of Medicinal Chemistry . 55 . 7 . 3331–3341 . April 2012 . 22409573 . 10.1021/jm300029s . American Chemical Society (ACS) .
  12. Heynen-Genel S, Dahl R, Shi S, Sauer M, Hariharan S, Sergienko E, Dad S, Chung TD, Stonich D, Su Y, Caron M, Zhao P, Abood ME, Barak LS . Selective GPR35 Antagonists - Probes 1 & 2 . Probe Reports from the NIH Molecular Libraries Program [Internet] . Bethesda (MD) . National Center for Biotechnology Information (US) . 2010 . 21433393 . Bookshelf ID NBK50703 .
  13. Jenkins L, Harries N, Lappin JE, MacKenzie AE, Neetoo-Isseljee Z, Southern C, McIver EG, Nicklin SA, Taylor DL, Milligan G . Antagonists of GPR35 display high species ortholog selectivity and varying modes of action . The Journal of Pharmacology and Experimental Therapeutics . 343 . 3 . 683–695 . December 2012 . 22967846 . 3500541 . 10.1124/jpet.112.198945 . American Society for Pharmacology & Experimental Therapeutics (ASPET) .
  14. Shrimpton AE, Braddock BR, Thomson LL, Stein CK, Hoo JJ . Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype . Clinical Genetics . 66 . 6 . 537–544 . December 2004 . 15521982 . 10.1111/j.1399-0004.2004.00363.x . 42975740 .
  15. Okumura S, Baba H, Kumada T, Nanmoku K, Nakajima H, Nakane Y, Hioki K, Ikenaka K . Cloning of a G-protein-coupled receptor that shows an activity to transform NIH3T3 cells and is expressed in gastric cancer cells . Cancer Science . 95 . 2 . 131–135 . February 2004 . 14965362 . 11159784 . 10.1111/j.1349-7006.2004.tb03193.x . 22753833 . free .

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